title: Chemoprevention of head and neck cancer with celecoxib and erlotinib: results of a phase ib and pharmacokinetic study.
abstract: Epidermal growth factor receptor (EGFR) and COX-2 inhibitors synergistically inhibit head and neck squamous cell carcinoma tumorigenesis in preclinical studies. We conducted a phase I and pharmacokinetic study with the erlotinib and celecoxib combination in patients with advanced premalignant lesions. Thirty-six subjects with oral leukoplakia, mild, moderate, or severe dysplasia, or carcinoma in situ were screened for study participation; 12 consented and received therapy for a median of 5.38 months. Erlotinib was escalated following a standard 3+3 design at 50, 75, and 100 mg orally daily and celecoxib was fixed at 400 mg twice daily for 6 months. Biopsy of lesions and cytobrush of normal mucosa were performed at baseline, 3, 6, and 12 months. Erlotinib pharmacokinetics were analyzed in 10 subjects. The maximum tolerated dose of erlotinib with celecoxib 400 mg BID was 50 mg per day with skin rash being the main observed toxicity. Overall histologic response rate was 63% (complete response, 43%; partial response, 14%; stable disease, 29%; and disease progression, 14%). With median follow-up of 36 months, mean time to progression to higher-grade dysplasia or carcinoma was 25.4 months. Downregulation of EGFR and p-ERK in follow-up biopsies correlated with response to treatment. Larger average erlotinib V/F (approximately 308 L) and CL/F (8.3 L/h) compared with previous studies may be related to relatively large average bodyweights. Average erlotinib t1/2 was 25.6 hours. Encouraging responses to the celecoxib and erlotinib combination correlated with EGFR pathway inhibition. Although erlotinib-related rash was the main limitation to dose escalation, the intervention was well tolerated.
authors.affiliation: Emory University School of Medicine, 1365 Clifton Road, Atlanta, GA 30322. dmshin@emory.edu.
authors.forename: Nabil F
authors.initials: NF
authors.lastname: Saba
authors.forename: Selwyn J
authors.initials: SJ
authors.lastname: Hurwitz
authors.forename: Scott A
authors.initials: SA
authors.lastname: Kono
authors.forename: Chung S
authors.initials: CS
authors.lastname: Yang
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Zhengjia
authors.initials: Z
authors.lastname: Chen
authors.forename: Gabe
authors.initials: G
authors.lastname: Sica
authors.forename: Susan
authors.initials: S
authors.lastname: Müller
authors.forename: Rachel
authors.initials: R
authors.lastname: Moreno-Williams
authors.forename: Melinda
authors.initials: M
authors.lastname: Lewis
authors.forename: William
authors.initials: W
authors.lastname: Grist
authors.forename: Amy Y
authors.initials: AY
authors.lastname: Chen
authors.forename: Charles E
authors.initials: CE
authors.lastname: Moore
authors.forename: Taofeek K
authors.initials: TK
authors.lastname: Owonikoko
authors.forename: Suresh
authors.initials: S
authors.lastname: Ramalingam
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Beitler
authors.forename: Sreenivas
authors.initials: S
authors.lastname: Nannapaneni
authors.forename: Hyung Ju C
authors.initials: HJ
authors.lastname: Shin
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: Zhuo Georgia
authors.initials: ZG
authors.lastname: Chen
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000517:prevention & control*; D000068579:Celecoxib; D018890:Chemoprevention / Q000379:methods*; D018450:Disease Progression; D000069347:Erlotinib Hydrochloride; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D011720:Pyrazoles; D011799:Quinazolines; D013449:Sulfonamides; D000069347:Erlotinib Hydrochloride; D000068579:Celecoxib